T-cell leukemias and lymphomas are clinically aggressive cancers resistant to conventional chemotherapy regimens and in desperate need for novel therapeutic approaches. This proposal studies the pathogenesis of these hematologic neoplasms and directly benefits Veterans' health by advancing the development of targeted therapy, and precision medicine for these treatment-resistant cancers. Our laboratory has been studying T-cell neoplasms from the perspective of two major oncogenic pathways: the LIM domain Only-2 (LMO2) pathway and the IL2RG/JAK1/3/STAT5 cytokine signaling pathway. LMO2 is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia. LMO2 encodes a small 18 kDa protein that is part of a large multisubunit protein complex that regulates the transcription of key target genes. We have been dissecting the mechanism by which LMO2's enforced expression induces T-ALL and have discovered key pre-leukemic phenotypes enforced by LMO2 like differentiation arrest and enhanced self-renewal. The IL2RG/JAK1/3/STAT5 pathway is required for the development and function of lymphocytes and our lab discovered that gain of function in this pathway is common in both mature and immature T-cell neoplasms. In recent exciting data, our LMO2 and JAK3 work has converged in intriguing findings. Mutational and gene expression analyses show that LMO2 overexpression and JAK3 activating mutations are concordant hits in both mature and immature T-cell neoplasms. The results imply that these two pathways cooperate to induce T- cell transformation. Interestingly, enforced expression of LMO2 in double negative T-cell progenitors induces highly penetrant T-cell leukemias but double positive progenitors do not develop leukemia. Similarly, enforced expression of constitutively active mutant JAK3 does not induce disease on its own. We hypothesize that T-cell transformation into leukemia or lymphomas may manifest if these two pathways were concordantly activated. In this proposal, we will investigate the mechanistic basis of this cooperativity so that T-cell leukemias and lymphomas may be better targeted therapeutically. In Aim 1, we will investigate the cooperativity between LMO2 and JAK3 oncogenes using bone marrow transduction and transplantation in our Lmo2 transgenic mouse model. In Aim 2, we will analyze signal transduction within the IL2RG/JAK1/3/STAT5 pathway in leukemias and lymphomas induced in Lmo2 transgenic mice. In Aim 3, we will test the use of JAK inhibitors against primary human T-cell neoplasms and analyze synergy with chemotherapy and LMO2 knockdown. The Aims will establish a foundation for the development of novel biomarkers and novel therapeutic approaches based on LMO2 and IL2RG/JAK1/3/STAT5 pathways.